Involvement of acyl-CoA thioester metabolite in drug-induced idiosyncratic liver injury

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08432
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kindai University
• Principal Investigator: Iwaki Masahiro 近畿大学, 薬学部, 教授 (30140346)
• Co-Investigator(Kenkyū-buntansha): 川瀬 篤史 近畿大学, 薬学部, 准教授 (80411578) ; 島田 紘明 近畿大学, 薬学部, 助教 (40783444)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 特異体質性肝毒性 / 反応性代謝物 / 非ステロイド性抗炎症薬 / 免疫細胞

Outline of Final Research Achievements

We focused on the acyl-CoA thioester metabolites of NSAIDs (NSAID-CoAs) as one of the cause of NSAID-induced idiosyncratic liver injury. Although we attempted to obtain NSAID-CoAs to evaluate their chemical reactivity, we could not synthesized NSAID-CoAs successfully by performing both biological and chemical experiments. On the other hand, NSAIDs inhibited acyl-CoA synthase activity quite weakly. In addition to NSAID-CoA, we also investigated contribution of acyl glucuronide metabolite of NSAIDs (NASID-AGs) to development of NSAID-induced idiosyncratic liver injury.
We clarified that the rate constant of enzymatic degradation of NSAID-AGs in rat liver microsomes well concern with the incidence of idiosyncratic toxicity of parent NSAIDs. Moreover, we demonstrated contribution of macrophage to NSAIDs-induced toxicity through AG generation in hepatocyte.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

患者の体質に依存して発症する特異体質性肝毒性は発症予測が非常に困難であり、発症に反応性代謝物の生成が寄与することは明らかにされているが、詳細な発症機構については未だ不明であった。特に市場に出て幅広い背景を有する患者が服用して初めて特異体質性肝毒性が惹起される場合があり、医薬品開発においても臨床においても緊喫に解決すべき課題である。本研究は特異体質性毒性の発症メカニズムの一端として、薬物の代謝経路ごとの寄与や免疫担当細胞の寄与を明らかにしたことで、医薬品開発における候補化合物の選定や臨床における副作用回避に有益な情報を与えるものである。